Biomedical subjects

Kenji Kosaka

Publications and source records attributed to Kenji Kosaka.

66 records · Page 4Linked to original sources

PubMed2002

Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies.

An approach was used to identify the oxidized nucleoside, 8-hydroxyguanosine in brains of dementia with Lewy bodies. Neurons with marked immunoreaction of 8-hydroxyguanosine in the cytoplasm were widely distributed in the hippocampal region and temporal neocortex. Relative intensity measurements of neuronal 8-hydroxyguanosine immunoreactivity showed that there was a significant increase in nucleic acid oxidation in dementia with Lewy bodies compared with controls. Treatment with nuclease (DNase or RNase) before the immunostaining demonstrated that RNA was a major site of nucleic acid oxidation. Together with the previously reported RNA oxidation in vulnerable neurons in Alzheimer and Parkinson diseases, neuronal RNA oxidation in dementia with Lewy bodies might represent one of the fundamental abnormalities in age-associated neurodegenerative diseases.

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PubMed2002

Immunohistochemical study of synphilin-1 in brains of patients with dementia with Lewy bodies - synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.

Dementia with Lewy bodies brains were immunohistochemically investigated using anti-synphilin-1 antibodies. The alpha-synuclein-positive brainstem type and well-defined cortical type Lewy bodies (LB) were positive for synphilin-1, while ill-defined LB and LB-related neurites were negative, suggesting that synphilin-1 does not directly associate with alpha-synuclein. Synphilin-1-positive LB were double-positive for phosphorylated neurofilament. In addition, tau-positive neurofibrillary tangles (NFT) were positive for synphilin-1, while neuropil threads were negative. Immunoelectron microscopically, synphilin-1 was located on filamentous components in cortical type LB and on paired helical filaments in NFT. It is likely that synphilin-1 accumulates in the cell body according to the axonal transport blockage, and associates with abnormal cytoskeltons during the formation of LB or NFT, suggesting that synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.

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PubMed2002

Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia.

The conventional concept of Pick's disease does not distinguish Pick's disease with Pick bodies (Pick body disease, PBD) from Pick's disease without Pick bodies [lobar atrophy without Pick bodies, LA-PB(-)]. Recently, intraneuronal ubiquitin-positive inclusions (ub-inclusions), which are thought to be a hallmark of amyotrophic lateral sclerosis with dementia (ALS-D), have been found also in LA-PB(-). We reconfirmed that ub-inclusions are consistently detected in LA-PB(-) as well as ALS-D. Subsequently, morphometric evaluation for involvement of the upper and lower motor neuron systems were performed in seven cases each of PBD, LA-PB(-), ALS-D and controls. As an indicator of upper motor neuron involvement, the total number of axons through the pyramis of the medulla oblongata was employed and for lower motor neuron involvement, the number of hypoglossal neurons per unit area was calculated. In LA-PB(-), axons of the pyramidal tract were significantly reduced in comparison to PBD and controls, while the lower motor neurons were preserved. Contrary to LA-PB(-), ALS-D revealed significant reduction of hypoglossal neurons but its pyramidal tract tends to be relatively preserved. These results seem to indicate that LA-PB(-) and ALS-D belong to the same spectrum and consist of subgroups with ub-inclusions and involvement of motor neuron system in common. The involvement of the upper motor neuron system is emphasized in LA-PB(-), while ALS-D accentuates the lower motor neuron system. However, the border between the two group is not always clear and there are patients who can not be definitively classified.

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PubMed2002

Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital.

Dementia is a social problem in Japan, as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not.

Age Factors↗

PubMed2002

Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies.

Using alpha-synuclein-immunohistochemistry, 27 brains of dementia with Lewy bodies (DLB) were investigated to identify the progression of Lewy pathology including Lewy bodies (LB) and LB-related neurites in the cerebrum. The numbers of alpha-synuclein-positive LB and LB-related neurites were semiquantitatively evaluated in the amygdala, hippocampus, entorhinal cortex, transentorhinal cortex, insular cortex, middle temporal cortex and superior frontal cortex. The results indicated that Lewy pathology within the neuron progresses first in the axonal terminal, subsequently in the cell body and finally in the dendrite, that Lewy pathology in the cerebral cortex progresses first in layers V-VI, subsequently in layer III and finally in layer II, and that Lewy pathology in the cerebrum progresses first in the amygdala, subsequently in the limbic cortex and finally in the neocortex. In addition, Lewy pathology was graded from stage I to stage IV based on the progression of Lewy pathology. The 27 brains examined were classified into 3 brains showing stage I, 11 showing stage II, 7 showing stage III and 6 showing stage IV. Comparing these stages with the pathological subtypes of DLB brains, brains of the subtype showing severe Alzheimer pathology corresponded to brains showing an advanced stage, suggesting that Alzheimer pathology exacerbates Lewy pathology.

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PubMed2002

Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains.

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.

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PubMed2002

Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases.

We investigated the occurrence of T cells in the brain parenchyma of Alzheimer's disease (AD), non-AD degenerative dementias and controls by semi-quantitative analysis of immunohistochemically stained tissue sections. In all cases, we found at least some T cells. The number of T cells was increased in the majority of AD cases compared with other cases. The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated. Antigen-triggered clonal expansion is not likely to take place. Local inflammatory conditions might cause accumulation and activation of T cells in the AD brain.

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PubMed2002

Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer's disease and limbic NFT dementia.

Brains of non-demented elderly people were divided into two groups according to the presence or absence of senile plaques (SP(+) and SP(-)). The regional number of NFT in each group were then quantitatively investigated and compared with that in the late-onset Alzheimer's disease (AD) group and the limbic NFT dementia (LNTD) group. NFT were divided into type 1, type 2 and type 3 according to the developmental stage. In addition, polymorphism of the apolipoprotein E (Apo E) gene was analyzed in all groups. The most frequent regions of NFT common to all groups were the transentorhinal cortex, the entorhinal cortex, the subiculum and cornu ammonis (CA)1 of the hippocampus. In the SP(+) group the proportion of type 3 was high in the transentorhinal cortex and entorhinal cortex, while type 1 or 2 were high in the subiculum and CA1, suggesting that NFT formation progresses from the parahippocampal cortex to the hippocampus. In the SP(-) group the proportion of type 3 was higher in the subiculum and CA1 than in the transentorhinal cortex and entorhinal cortex, suggesting that NFT formation is accelerated in the hippocampus. The late-onset AD group and LNTD group showed the patterns of NFT formation similar to those of the SP(+) group and SP(-) group, respectively. The frequency of the epsilon4 allele of the Apo E gene was significantly higher in the late-onset AD group and SP(+) group than in the LNTD group and SP(-) group, respectively. From these findings it is suggested that persons in the SP(+) group are likely to remain non-demented elderly persons or become a developmental matrix of late-onset AD with a risk factor of the epsilon4 allele, while those in the SP(-) group are likely to remain non-demented elderly persons or pass into LNTD without a risk factor of the epsilon4 allele.

Age of Onset↗

PubMed2002

Characterizing CGI-94 (comparative gene identification-94) which is down-regulated in the hippocampus of early stage Alzheimer's disease brain.

The treatment of Alzheimer's disease (AD) remains a major challenge because of the incomplete understanding of the triggering events that lead to the selective neurodegeneration characteristic of AD brains. Here we describe a new protein, CGI-94, that is down-regulated at the mRNA level in the hippocampus of early stage AD brain. Transfection experiments with CGI-94 as a green fluorescent protein (GFP)-fusion-protein show that this protein is translocated into the nucleus of the cell. The finding that this protein, which has a bipartite nuclear localization signal, is also observed in the cytoplasm and extracellular space points to a multifunctional protein. Immunohistochemical analyses reveal that CGI-94 is mainly expressed in neurons of the hippocampal formation and the cortex but not in the cerebellar nucleus. In conclusion, the expression of the nucleolar phosphoprotein CGI-94 appears to be disturbed in early processes of neuronal degeneration.

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PubMed2002

Methamphetamine in Japan: the consequences of methamphetamine abuse as a function of route of administration.

AIMS: To determine differences in life backgrounds and clinical features between methamphetamine (MAP) smokers and injectors in Japan. SETTING: Out-patient clinic at a psychiatric centre. PARTICIPANTS: Among 451 MAP abusers undergoing initial assessments, 116 subjects whom the first author had directly interviewed and treated were studied. DESIGN AND PROCEDURES: In this study, life backgrounds, clinical features and psychiatric symptoms were compared between three subgroups: 42 (36.2%) in group S (smoking only); 57 (49.1%) in group I (injection only); and 17 (14.7%) in group SI (initially smoking, later injecting). FINDINGS: Group I more often had parental absence (P < 0.001), a family history of alcoholism (P < 0.05), limited education (P < 0.001), or a criminal record (P < 0.001) than patients in the other two groups. Group S had the most cannabis use (P < 0.01), while group I had the most volatile solvents use (P < 0.01). Group S experienced their first psychotic episode sooner after first MAP use (P < 0.01), but showed fewer auditory hallucinations at initial assessment than patients in other groups (P < 0.001). Group SI was intermediate between groups S and I in life background, clinical features and psychotic symptoms, while they had lost control of their drug use most frequently (P < 0.02). CONCLUSIONS: In Japan, MAP smokers have different life backgrounds from injectors. Smoking MAP does not appear to be a safer route as regards losing control of MAP use and inducing psychosis than injection.

Adolescent↗

PubMed2002

Degeneration of Pick bodies visualized by methenamine-silver staining and immunohistochemistry.

The degeneration process of Pick's bodies (PB) was investigated using methenamine-silver (MS) staining and immunohistochemistry. Methenamine-silver staining sensitively detected extracellular PB as well as intracellular PB in the granular cell layer of the dentate gyrus. Extracellular PB appeared as granular masses with ill-defined boundaries in the neuropil. For MS electron microscopy, the extracellular PB were composed of randomly oriented fibrillary components measuring 9-12 nm in diameter with astroglial processes and degenerated organelles. Tau immunoreactivity of extracellular PB was reduced or abolished. These findings indicate that MS staining is a convenient method for detecting extracellular PB. In addition, it was shown that microglial involvement was associated with PB-bearing neurons at the late stage of the degeneration process and that extracellular PB remained in the neuropil with astroglial reaction.

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PubMed2002

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: comparison with late-onset Alzheimer's disease brains.

We quantitatively investigated the formation process of neurofibrillary tangles (NFT) in the hippocampus of 32 brains from non-demented elderly persons using tau-immunohistochemistry, compared with 13 brains from patients with late-onset Alzheimer's disease (AD). The 32 non-demented elderly brains were classified into 16 brains in group I and 16 brains in group II mainly based on the distribution of tau-positive neurons in the hippocampus. Tau-positive neurons were found predominantly in the CA2 in group I, while they were found predominantly in the subiculum-pre-CA1 in group II. Most late-onset AD brains showed a distribution of tau-positive neurons similar to that in group II. In addition, the distribution pattern of tau-positive neurons in the hippocampus was closely related to degeneration of the perforant pathway with the accumulation of tau. These findings suggest that NFT occur first in the CA2 and extend to the subiculum-pre-CA1 in group I, while they occur first in the subiculum-pre-CA1 and extend to the CA2 later in group II, and that the NFT occurring in the subiculum-pre-CA1 are mainly related to degeneration of the perforating route and in the CA2 are related to the degeneration of the non-perforating route.

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